Hippocampal-Avoidance Using Intensity-Modulated Radiation Therapy for the Treatment of Low-Grade Glioma

Status: active

This phase II trial studies the benefits of avoiding the hippocampus during intensity-modulated radiation therapy (proton therapy) for patients with low-grade glioma. The hippocampus is a brain structure that is important for memory. Research has shown that hippocampal avoidance may preserve memory in adults. The purpose of this study is to find out what happens, good and bad, to memory and learning when the hippocampus is avoided during proton therapy radiation in children, adolescents, and young adults. Intensity-modulated radiation therapy uses high energy protons to kill tumor cells and shrink tumors. Doctors hope that planning radiation treatment to avoid the hippocampus will be a way to prevent loss of memory and learning ability after radiation treatment to the brain.

Inclusion Criteria

Patients must have a diagnosis of pilocytic astrocytoma, pilomyxoid astrocytoma, pleomorphic xanthoastrocytoma, ganglioglioma, optic pathway glioma, diffuse astrocytoma, low-grade neuroepithelial tumor, low-grade glioneuronal tumor or low-grade glioma, not otherwise specified (NOS), after central pathology review; if applicable
Patients must have had histologic verification of disease at original diagnosis or recurrence. Patients with optic pathway gliomas and tumors of the brainstem/midbrain/tectum can be enrolled without histologic verification but with radiologic verification
If there is a high index of suspicion regarding high grade transformation, repeat biopsy is required
Tumor must be located in or adjacent to the suprasellar region or midline structures. Midline structures include, but are not limited to: thalamus, basal ganglia, internal capsule, medial temporal lobe, midbrain, tectum, third ventricle, fourth ventricle, cerebellum, pons and medulla. Tumors may involve the optic pathway. For questions about tumor locations that are not specified on this list, please contact study principal investigator (PI)
Patients must be aged 6 to < 22 years at the time of enrollment
Patients must have a performance status greater or equal to 70 (use Karnofsky scale for patients aged 16 years and greater, and Lansky scale for patients aged less than 16 years)
Patients may not receive concurrent chemotherapy or targeted therapy, including but not limited to, BRAF- inhibitors and MEK- inhibitors
All patients must be able to undergo contrast-enhanced brain magnetic resonance imaging (MRI)
Patients with seizures may be enrolled if well controlled on anticonvulsants

Exclusion Criteria

Patients who have received prior central nervous system (CNS) radiation
Patients with gross total resection and no measurable disease on MRI
Patients with evidence of metastatic disease
Patients with: World Health Organization (WHO) grade II midline tumors that harbor histone H3 K27M mutation, IDH-mutant gliomas, grade II ependymoma and subependymoma, pituicytoma, spindle cell oncocytoma, granular cell tumor of the sellar region
Patients with tumors that directly invade the hippocampus or where the gross tumor volume extends into the hippocampus
Patients with tumors in the spinal cord or cervicomedullary junction
Females of child-bearing potential cannot be pregnant or breast-feeding. Female participants > 10 years of age or post-menarche must have a negative serum or urine pregnancy test prior to enrollment. Males and females of reproductive potential may not participate unless they have agreed to use an effective contraceptive method
Patients who are status post resection of bilateral hippocampi. Patients who are status post resection of one hippocampus will be eligible for the study and the hippocampal dose constraints will be applied to the intact hippocampus

PRIMARY OBJECTIVE:

I. To determine the feasibility of hippocampal-avoidance (HA) using proton therapy in suprasellar or midline low-grade gliomas (LGGs).

SECONDARY OBJECTIVES:

I. To estimate the 3-year event free survival (EFS) of LGG treated with HA.

II. To estimate the change in California Verbal Learning Test short-term delay (CVLT-SD) scores from baseline to 3 years and from baseline to 5 years.

III. To compare CVLT-SD and Cogstate neurocognitive scores in patients with proton therapy plans that: (1) meet first priority radiation therapy (RT) dose constraints, (2) meet second priority RT dose constraints but not first priority RT dose constraints, and (3) that did not meet either first or second RT priority dose constraints.

EXPLORATORY OBJECTIVES:

I. To describe the change in overall cognitive performance from baseline to 3 years and from baseline to 5 years with an age appropriate battery, including gold standard measures shown in the published studies to be sensitive to attention, memory processing speed and executive function that will afford comparison to historical controls.

II. To characterize longitudinal changes in connection strength within brain networks in the first 3 years after proton therapy and to investigate associations between these changes and neurocognitive performance with focus on the hippocampi.

III. To correlate the distribution and change in L-methyl-11C-methionine positron emission tomography (MET-PET) uptake to tumor progression from baseline to 3 years and to investigate whether cases of pseudoprogression exhibit a differential pattern of uptake and distribution than do cases of true progression after controlling for histology.

IV. To investigate the effect of BRAF alteration, tumor histology and tumor location on progression-free survival (PFS) and overall survival (OS) in a prospective cohort of patients treated in a homogenous manner.

V. To investigate whether the methylation profiles of LGG differ across tumor locations (thalamic/midbrain versus [vs.] hypothalamic/optic pathway vs. others) and histologies (pilocytic astrocytoma vs. diffuse astrocytoma vs. others), which in conjunction with specific genetic alterations may stratify patients into different subgroups and highlight different therapeutic targets.

VI. To record longitudinal measures of circulating tumor (ctDNA) in plasma and correlate these measures with radiographic evidence of disease progression.

VII. To bank formalin-fixed, paraffin-embedded (FFPE)/frozen tumors and whole blood from subjects for subsequent biology studies not currently defined in this protocol.

VIII. To quantify and characterize tumor infiltrating lymphocytes (TILs) and to characterize the epigenetics of T cells and the T-cell receptor repertoire within the tumor microenvironment.

IX. To estimate the cumulative incidence of endocrine deficiencies, vision loss, hearing loss and vasculopathy after proton therapy and compare these data to those after photon therapy.

OUTLINE:

Patients undergo 29-30 fractions of intensity-modulated radiation therapy over 30-50 minutes 5 days per week, Monday-Friday for up to 6 weeks in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 12 weeks for 2 years and then every 6 months for up to 3 years.

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Hippocampal-Avoidance Using Intensity-Modulated Radiation Therapy for the Treatment of Low-Grade Glioma

Inclusion Criteria

Exclusion Criteria

United States

Tennessee

Memphis

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Hippocampal-Avoidance Using Intensity-Modulated Radiation Therapy for the Treatment of Low-Grade Glioma

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